Diabetes mellitus is a disease of a major global importance. The number of individuals affected increases at almost epidemic rates, such that in 2006, this number reached approximately 170 million people worldwide and is predicted to at least double over the next 10-15 years. Diabetes is characterized by a chronically raised blood glucose concentration (hyperglycemia), due to a relative or absolute lack of the pancreatic hormone-insulin. Within healthy pancreas, beta cells that are located in the islets of Langerhans and continuously produce and secrete insulin according to the blood glucose levels, thereby maintaining near constant levels of glucose in the body. Long-term tissue complication affects both the small blood vessels (microangiopathy, causing eye, kidney and nerve damage) and the large blood vessels (causing accelerated atherosclerosis, with increased rates of coronary heart disease, peripheral vascular disease and stroke). These complications heavily burden the patients and health care resources that are necessary to treat the patients.
The Diabetes Control and Complications Trial (DCCT) demonstrated that development and progression of chronic complications of diabetes are heavily related to the degree of altered glycemia, as quantified by determinations of glycohemoglobin (HbA1c). [DCCT Trial, N Engl J Med 1993; 329: 977-986, UKPDS Trial, Lancet 1998; 352: 837-853. BMJ 1998; 317, (7160): 703-13 and the EDIC Trial, N Engl J Med 2005; 353, (25): 2643-53]. Thus, maintaining normoglycemia, which may be accomplished by frequently measuring glucose levels and accordingly adjusting an amount of delivered insulin, is of utmost importance. Conventional insulin pumps can deliver insulin to the patient and can be configured to deliver rapid-acting insulin 24 hours a day through a catheter placed under the skin. The total daily insulin dose can be divided into basal and bolus doses. Basal insulin is delivered continuously over 24 hours and keeps the blood glucose concentration levels (hereinafter, “blood glucose levels”) in normal desirable range between meals as well as overnight. Diurnal basal rates can be pre-programmed or manually changed according to various daily activities of the patient. Insulin bolus doses are delivered before or after meals to counteract carbohydrates loads or during periods of high blood glucose concentration levels.
The bullet list below provides a sample of parameters that can be used to select the insulin bolus dose.                Amount of carbohydrates (“carbs”) to be consumed. For example, the amount of carbohydrates can be defined as “servings”, wherein 1 serving equals 15 grams of carbohydrates.        Carbohydrate-to-insulin ratio (“CIR”) that represents an amount of carbohydrates balanced by one unit of insulin. CIR can be measured in grams per one unit of insulin.        Insulin sensitivity (“IS”), i.e., an amount of blood glucose lowered by one unit of insulin. IS can be measured in mg/dL (milligrams/deciliter) per one unit of insulin.        Current blood glucose levels (CBG). CBG can be measured in mg/dL.        Target blood glucose levels (TBG), i.e., a desired blood glucose level, which can be measured in mg/dL. TBG for some patients with diabetes is in the range of 90-130 mg/dL before a meal, and less than 180 mg/dL one to two hours after the beginning of a meal.        Residual insulin (RI), i.e., an amount of stored active insulin remaining in the body of the patient after a recent bolus delivery. For example, this parameter can be relevant when there is a short time interval between consecutive bolus doses (e.g., less than 5 hours).        
Conventional insulin pumps require its users to constantly calculate or estimate appropriate pre-meal insulin bolus doses. These calculations or estimations can be based on the above-mentioned parameters, which help provide effective control of the blood glucose levels and, thus, maintenance of normoglycemia. Conventional portable insulin pumps include bolus calculating means that operate based on inputs of meal carbohydrate content and glucose levels by the patient. In these pumps, the calculated bolus dose is automatically calculated and delivered to the patient.
An example of such conventional pumps is discussed in U.S. Pat. No. 6,936,029. An algorithm implemented in the conventional pumps is based on a formula for calculating the recommended bolus dose, depending on the user's IS, CIR, target blood glucose (TBG) and user inputs of BG and Carbs intake. If the current BG is higher than the target BG, the recommended bolus is calculated as follows:
                              recommended          ⁢                                          ⁢          bolus                =                                                            (                                  T                  ⁢                                                                          ⁢                                      C                    /                    C                                    ⁢                                                                          ⁢                  I                  ⁢                                                                          ⁢                  R                                )                            ︸                                      Food              ⁢                                                          ⁢              Estimate                                +                                                                      (                                                            C                      ⁢                                                                                          ⁢                      B                      ⁢                                                                                          ⁢                      G                                        -                                          T                      ⁢                                                                                          ⁢                      B                      ⁢                                                                                          ⁢                      G                                                        )                                /                I                            ⁢                                                          ⁢              S                                      ︸                              Correction                ⁢                                                                  ⁢                Estimate                                              -                      R            ⁢                                                  ⁢            I                                              (        1        )            where “TC” is a total amount of carbohydrates; “CIR” is a carbohydrate-to-insulin ratio; “TBG” is a target blood sugar; “CBG” is a current blood sugar; “IS” is an insulin sensitivity; “RI” is a residual insulin.
If the current BG is lower than the target BG, the recommended bolus is calculated as:recommended bolus=(TC/CIR)+(CBG−TBG)/IS  (2)
If the current BG is higher than the low target BG and lower than the high target BG (e.g., current blood glucose=105 mg/dL, target blood glucose=90-130 mg/dL) then the recommended bolus is calculated as:recommended bolus=(TC/CIR)+0  (3)
An accurate assessment of the CIR is essential for determining the recommended bolus dose by the above formulas, and specifically by its “food estimate” portion (See, Equation (1)).
CIR can currently be determined by many type-1 diabetes patients using rapid acting insulin (e.g., Humalog, Novolog) according to the so-called “450 to 500 rules”. The patient's CIR can be established by dividing the value corresponding to appropriate “rule” by the total daily dose of rapid-acting insulin. For example, if the total daily insulin dose is 40 Units and the “450 rule” is used, the CIR would approximately equal to 11 grams (i.e., 450 divided by 40).
For example, Table 1 illustrates the Carbs (in grams) covered by 1 Unit of insulin (CIR) according to various “rules”. (Table 1 is adapted from Using Insulin, Everything You Need for Success with Insulin, by J. Walsh, R. Roberts, C. B. Varma and T. Bailey, Torrey Pines Press, 2003).
TABLE 1Carbohydrate-to-insulin ratios according to various “rules”,where Carbs are covered by 1 Unit of insulin.Total daily insulin dose(TDD) [IU/day]500 Rule450 Rule202523252018301715351413401311501096088
The accuracy of the CIR calculated by “rules” is very low because the “rules” are not patient-specific. Additionally, a number of applied “rules” is limited. Thus, for every bolus delivery, an over/under Carbs load-estimation error is further augmented by the inaccuracy of the CIR. The CIR values are often changed, especially in adolescents. Currently, the “rule”-derived CIR value is programmed only once—during the pump initiation. The “rule” is not re-evaluated throughout the usage of the bolus calculator. Thus, a serious hazard of over/under bolus dosing should be further taken into consideration.
Accurate assessments of changes in CIR values over time enable better follow-up and improved glycemic control.